SUMMARY Oligodendrocytes and neurons rely on one another for metabolite exchange and for synaptodendritic connectivity. A key factor for these functions is retinoic acid (RA), also known as vitamin A. Previous studies show that cocaine use and HIV infection independently disrupt RA metabolism. White matter loss is often observed in individuals with cocaine abuse disorder and in HIV infected individuals. Cocaine use is a major risk factor for becoming infected with HIV and the use of cocaine during HIV infection worsens and speeds up HIV-associated CNS disease. Our new data show that cocaine and the HIV protein Tat significantly disrupt RA signaling in oligodendrocytes, leading to energy deficits and decreased capacity of oligodendrocytes to provide metabolic support to neurons. The RA degrading enzyme, Cyp26A1 is significantly increased by cocaine and by Tat resulting in decreased bioavailable RA to affect at least two RA-mediated signaling pathways in oligodendrocytes. First, we found that cocaine and Tat significantly inhibit RA-mediated activation of AMPK, the energy sensor of the cell. Loss of AMPK activity reduces pyruvate levels, resulting in decreased ATP production, fatty acid biosynthesis and lactate transfer to neurons, all of which impair myelin integrity and axonal fitness. Second, cocaine and Tat interfere with RA nuclear receptor-mediated gene transcription of myelin proteins and with the neuroplasticity proteins Neurogranin and GAP-43. Together, these data support our hypothesis that cocaine and Tat work together to impair RA signaling in oligodendrocytes leading to disruption of oligodendrocyte-neurons metabolic coupling. Importantly, our data also show that treating oligodendrocytes and neurons with clinically approved RA (vitamin A) supplements alleviates some of these signaling disruptions. For example, we have shown that 9-cis-RA decreases lipid peroxidation and promotes oligodendrocyte survival. Results from our studies may lead to improved treatment strategies for HIV infected individuals with cocaine abuse disorder by taking advantage of clinically approved and commonly used vitamin A supplementation to target disruptions in RA metabolism.